Confronting bla_NDM-5 in Salmonella Typhi: From Molecular Epidemiology, Resistance Mechanism to Clinical Management

Introduction

Global Burden of Disease from Salmonella Typhi Infection

Typhoid fever, caused by Salmonella Typhi, continues to pose a significant global health threat, particularly in low- and middle-income countries (LMICs) of South Asia, Southeast Asia, and sub-Saharan Africa.^1,2 The World Health Organization (WHO) has classified drug-resistant Salmonella Typhi as a high-priority pathogen, underscoring the urgency of this challenge.³ The disease burden is substantial, with an estimated 11 to 21 million cases and 128,000 to 161,000 deaths annually.² Beyond mortality, the economic and social impacts are profound. The annual cost of illness associated with typhoid fever is considerable, encompassing direct medical expenses and indirect productivity losses. Furthermore, the disability-adjusted life years (DALYs) lost due to typhoid, particularly its drug-resistant forms, highlight its severe impact on healthy life expectancy. For instance, reports from the CDC indicate that drug-resistant infections lead to longer hospitalizations and poorer outcomes, exacerbating this burden (doi: 10.15585/mmwr.mm7207a2). The evolution of Salmonella Typhi from classical multidrug resistance (MDR) to carbapenem resistance represents a critical escalation.^4,5 The failure of carbapenems, the last line of defense, marks a new era in the treatment crisis and underscores the pressing need for this review (Figure 1).^6,7

Figure 1 Air travel from Pakistan was used as a proxy for the risk of XDR typhoid introduction, while the estimated typhoid burden was used as a proxy for the risk of onward transmission and local outbreaks. Source data available in a separate file. Reproduced with permission. Copyright 2023, Springer Nature.

The Global Epidemic Trend of Carbapenem-Resistant Salmonella Typhi

From the classical multidrug resistance (MDR) chloramphenicol/ampicillin/trimethoprim-sulfamethoxazole (TMP-SMX), there has been a notable evolution towards carbapenem resistance. Carbapenem antibiotics were previously regarded as the last line of defense, and their failure marks a comprehensive escalation in the treatment crisis.⁵ Notably, the emergence of CR Salmonella enterica var typhi represents a distinct manifestation of the carbapenem-resistant Enterobacteriaceae (CRE) crisis, posing a threat that exceeds that of typical CRE due to its combination of high pathogenicity and extensivedrug resistance.

The emergence and global spread of CR Salmonella enterica var typhi were formally confirmed in 2018 when Klemm et al used whole-genome sequencing (WGS) to identify a strain isolated from a child in Pakistan in 2016.⁵ The subsequent case report from Pakistan, the recognized epicenter of the CR Salmonella enterica var typhi epidemic, revealed the clinical severity of CR Salmonella enterica var typhi infection.⁸ Genomic surveillance has confirmed the rapid spread of the H58 lineage clone carrying the bla_NDM-5 gene on IncX3 within Pakistan.⁴

Although other carbapenemase genes, such as bla_NDM-1, bla_VIM, bla_KPC, bla_OXA-48, and bla_IMP, are frequently identified in various Enterobacteriaceae, their presence in Salmonella Typhi remains exceedingly rare. To date, the vast majority of carbapenem-resistant Salmonella Typhi isolates worldwide carry bla_NDM-5, highlighting its dominant role in the current epidemiology. The sporadic reports of other carbapenemases in non-typhoidal Salmonella serovars (discussed below) underscore the potential for horizontal transfer, but they have not yet become established in Salmonella Typhi.

While local infections of CR Salmonella enterica var typhi in neighboring India are extremely rare (the first case was reported in Bangalore in 2025, belonging to the input-related H58 lineage), the region faces a continuous threat due to the backdrop of carbapenem-resistant Enterobacteriaceae epidemics and the environmental prevalence of NDM genes. The identification of homologous, bla_NDM-5-harboring IncX3 plasmids in strains from both India and Pakistan underscores the ongoing risk of cross-border transmission.^9–11

Other countries primarily report imported cases, involving international travelers or individuals returning from epidemic areas. For instance, countries such as the United Kingdom, the United States, and Canada have reported travel-related cases.¹² In 2022, Denmark first reported an imported case involving a pregnant woman.¹³ This pattern of global dispersal heightens vigilance worldwide. In China, although surveillance data from 2015 to 2022 identified only two bla_NDM-5-positive strains among 3695 Salmonella isolates,¹⁴ Salmonella Typhimurium (ST34 clone) carrying bla_NDM-5 has been detected in retail pork, indicating that the animal-food chain may serve as a potential transmission route.^15,16 Additionally, non-typhoidal Salmonella from animal sources (such as pigs and chickens) carrying carbapenemase genes have been reported in various regions worldwide, including China,^15–18 Germany,^19,20 and Iraq,²¹ indicating the potential risk of the horizontal transfer of antibiotic resistance genes to Salmonella Typhi.^16,17

The Discovery of bla_NDM-5 and Its Significance in Salmonella Typhi

The resistance of CR Salmonella enterica var typhi to carbapenem antibiotics primarily arises from the production of carbapenemases, with metallo-β-lactamases (MBLs) being the most prevalent. Among MBLs, the New Delhi metallo-β-lactamase (NDM) type dominates, accounting for over 96.7% of CR Salmonella enterica var typhi cases, with the NDM-5 variant being particularly common (Figure 2).^22–24

Figure 2 Phylogenetic analysis of Salmonella enterica strains, including Salmonella Typhimurium ST19 and ST34 isolates from NCBI, alongside local strains. The figure illustrates the relationship between different Salmonella serotypes. The blaNDM-carrying status, sequence type (ST), host, isolation time, and region are represented by squares of different colors. Note that ST19 and ST34 are characteristic of Salmonella Typhimurium.

NDM enzymes can efficiently hydrolyze nearly all β-lactam antibiotics, including carbapenems, the last-resort treatments for multidrug-resistant typhoid. This gene encoding NDM-5 was initially identified in Salmonella Typhi isolated from a patient in Pakistan, marking a pivotal moment in the evolution of drug-resistant typhoid. It is reported that the bla_NDM-5 gene often co-occurs with resistance to fluoroquinolones and cephalosporins, creating extensively drug-resistant (XDR) phenotypes that significantly elevate the risk of treatment failure and mortality.⁹

Genomic analysis has shown that Salmonella Typhi strains carrying bla_NDM-5 typically belong to the H58 haplotype, which is currently the globally prevalent antibiotic-resistant lineage.⁹ Additionally, bla_NDM-5 is often co-located with antibiotic resistance genes such as aac(6′)-Ia, and may be transmitted between different strains via InCX3-type plasmids, which increases the risk of its sustained dissemination in both hospital and community settings. Therefore, continuous genomic surveillance is crucial for tracking the transmission dynamics of bla_NDM-5 positive Salmonella Typhi and guiding treatment strategies.^9,25

The Molecular Epidemiological Characteristics of bla_NDM-5 Positive Salmonella Typhi in China

Geographical Distribution and Time Trend Analysis

Since the bla_NDM-5 gene was first detected in Salmonella from food sources in 2016, its detection frequency in Salmonella in China has gradually increased, involving multiple sources such as environment,¹⁷ clinical,¹⁸ poultry²⁶ and food.¹⁵ Between 2015 and 2022, two strains of Salmonella enterica carrying the bla_NDM-5 gene were isolated from a total of 3695 strains, confirming the introduction of such resistant bacteria into Chinese healthcare settings.¹⁴ Genomic analyses revealed that these clinical strains are closely related to the XDR Salmonella enterica var typhi clones responsible for outbreaks in Pakistan and India, indicating a clear risk of cross-border transmission.^14,27 Currently, reports of bla_NDM-5 positive Salmonella Typhi in China have primarily been are mainly concentrated in the eastern coastal regions, which aligns with the characteristics of frequent international travel and dense medical resources in these areas.¹⁴ The main detections of the bla_NDM-5 gene in various Salmonella serotypes (including Typhi and Typhimurium) across China are shown in Table 1.^{15–18,22,24,26,28–30}

Table 1 The Main Detection of blaNDM-5 Gene in Salmonella in China

MLST Typing Characteristics of the Main Epidemic Strains

Genomic analysis indicates that the bla_NDM-5 positive Salmonella Typhi identified in China primarily belongs to the H58 haplotype, which is characterized by the presence of multiple drug resistance genes.³¹ Specifically, the ST20 strain accounts for a certain proportion of carbapenem-resistant bacterial strains in China.³² In line with global trends, these strains often carry the gyrAS83Y mutation, which leads to resistance to fluoroquinolone antibiotics.³³ Notably, the Chinese isolates exhibited a high genomic similarity with the XDR Salmonella Typhi strains prevalent in the South Asian region, particularly the strains from the outbreak in Pakistan in 2016, indicating a potential common evolutionary origin.²⁷ It is important to clarify that while this review focuses on Salmonella Typhi, comparative genomic analyses often include other serotypes. For instance, as shown in Figure 2 (adapted from Ke et al), ST19 and ST34 strains are Salmonella Typhimurium, highlighting the broader context of bla_NDM-5 dissemination across different Salmonella serovars.²²

Multidrug Resistance Spectrum Characteristics of Clinical Isolates

Clinical isolates of bla_NDM-5 positive Salmonella Typhi in China exhibit an extensively drug-resistant (XDR) profile, characterized by multidrug resistance to ampicillin, ciprofloxacin, ceftriaxone, tetracycline, and meropenem, but typically remain susceptible to azithromycin and other alternative agents such as chloramphenicol and co-trimoxazole.^27,34 These strains often carry aminoglycoside-modifying enzyme genes, such as aac(6′)-Ia, resulting in cross-resistance.^33,34 Molecular epidemiological investigations have revealed that approximately 37.5% of the resistant strains carry the extended-spectrum β-lactamase gene bla_CTX-M-15 gene, further compromising β-lactam efficacy.³⁵ Notably, certain strains have disseminated the bla_NDM-1 gene via IncFII(Yp) type plasmids, which have been detected in 46 strains of diverse sequence types across six sentinel monitoring sites, highlighting a parallel route for the spread of carbapenem resistance in Salmonella³⁵ The primary resistance mechanisms and their genetic contexts are summarized in Figure 3.²⁸

Figure 3 The genetic surroundings of blaNDM-5 are depicted by diverse colored arrows, each denoting different open reading frames (ORFs) with the arrow’s orientation indicating transcription direction. Homogeneous areas are shown with light gray shading. Reproduced with permission. Copyright 2023, mSphere.

The Genetic Vector Structure and Transmission Elements of bla_NDM-5

The Core Genetic Structure of bla_NDM-5

The bla_NDM-5 gene is typically situated within a complex genetic context, characterized by its core structure, which comprises multiple insertion sequences (IS) and auxiliary genes. Notably, bla_NDM-5 is frequently associated with the ble_MBL (bleomycin resistance gene) and trpF (phosphoribosyl anthranilic acid isomerase gene), forming a stable gene cluster.^36–38 In addition, the genetic background of bla_NDM-5 often contains insertion sequences such as IS26, IS5, ISAba125 and IS3000, which play a key role in horizontal gene transfer and recombination.^28,39

Plasmid Type Analysis

In popular clones of CR Salmonella enterica var typhi, the bla_NDM-5 gene is primarily located on plasmids, which is a key factor for its efficient horizontal gene transfer (HGT) among different bacteria. The most common vector for the bla_NDM-5 gene in Salmonella Typhi in China is the IncX3 type plasmid, which encodes a type IV secretion system (T4SS) responsible for plasmid conjugative transfer.⁴⁰ Research by Gao et al has shown that the T4SS of IncX3 plasmids in certain Enterobacterales exhibits a phenomenon of apparent silencing, which may reduce the fitness burden on the host bacterium, thereby promoting the plasmid’s stable persistence and widespread dissemination within bacterial populations.⁴⁰ This mechanism, observed in related species, is hypothesized to similarly contribute to the successful dissemination of IncX3 plasmids carrying bla_NDM-5 in Salmonella Typhi. Additionally, bla_NDM-5 has been found on IncFIA/FIB/IncFII fusion plasmids,¹⁶ with certain clinical isolates carrying as many as 5–10 copies of the bla_NDM-5 gene.^41,42 Notably, a study on Salmonella Typhi isolates from India identified the presence of the InCX3 plasmid carrying bla_NDM-5,⁹ indicating the widespread distribution of this plasmid type in Asia. As stated in the literature, IncHI2-type plasmids are widely disseminated in the livestock-food chain across Asia, particularly in China,²⁴ and the IncHI2/ST3 plasmid disseminates the bla_NDM-5 gene among various Enterobacteriaceae species. IncX3¹⁸ and IncFII-type plasmids have also been found to carry the bla_NDM gene in human and animal/foodborne Salmonella, indicating their significant role in the cross-ecological transmission of antibiotic resistance genes.^16,43 As shown in Figure 4b, there are similarities in the genetic structure of bla_NDM-5 gene in different plasmids.

Figure 4 (a) Genetic structure of blaNDM-5 gene; (b) genetic structure of blaNDM-5 gene in different plasmids. * Xiang et al, 2023, Harada et al, 2024, ** Yang et al, 2022, Shin et al, 2023, *** Huang et al, 2025, ****Tang et al, 2024, Gonzalez et al, 2025.

Structural Characteristics of Transposon Complex

The bla_NDM-5 gene is commonly located within the structure of IS composite transposons.^16,44 Research has shown that the bla_NDM-5 region is situated on a composite transposon formed by IS elements, which includes a deletion of 366 bp in the Rep A protein-coding region. This structural variation may affect plasmid replication.⁴⁵ In other Enterobacteriaceae, the dissemination of the bla_NDM gene is primarily driven by the jumping of plasmid-borne transposons, followed by a restriction in plasmid exchange, which may be attributed to the adaptability of plasmids to their specific bacterial hosts.⁴⁶ Experimental evidence indicates that the replicative transposition of Tn and IS elements facilitates the horizontal transfer of bla_NDM and the evolution of plasmids that produce KPC-2.⁴⁷ Similar composite transposon structures carrying bla_NDM-5 have been identified in other Salmonella serovars (eg., Salmonella Typhimurium of porcine origin in China), reflecting the diversity of resistance element evolution. However, the primary focus of this review remains on Salmonella Typhi. Research indicates that the genetic environment of bla_NDM-5 in CR Salmonella enterica var typhi is highly similar to that found in other Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, strongly suggesting the interspecies transmission of antibiotic resistance genes.¹⁶ As shown in Figure 4a, the bla_NDM-5 gene is often embedded in composite transposons, which are composed of multiple IS elements and auxiliary genes. For example, Tn7051 is a new type of transposon, its structure is IS3000-ΔISAba125-IS5-ΔISAba125-bla_NDM-5-ble_MBL-trpF-ΔIS26-ΔumuD-ΔISKox3-IS3000.³⁷ This transposon was first discovered in IncHI2 plasmid and may play a key role in the transfer of bla_NDM-5 gene from IncX3 plasmid to IncHI2 plasmid. In addition, in some IncFIB plasmids, the bla_NDM-5 gene was inserted into the Tn1548-like transposon,⁴⁸ and its structure was IS26-bla_NDM-5-ble_MBL-trpF-dsbD-ISCR1-sul1-aadA2-dfrA12-IntI1-IS2.

While the bla_NDM-5 gene in Salmonella is predominantly plasmid-borne, studies in other Enterobacteriaceae have demonstrated its potential for chromosomal integration. For instance, Kong et al elucidated the chromosomal integration mechanism of bla_NDM-1 in Proteus vulgaris through the SXT/R391 ICE.⁴⁹ In Escherichia coli, the bla_NDM-5 gene has been found inserted into the chromosome flanked by IS26 elements. Although direct evidence of chromosomal integration of bla_NDM-5 in Salmonella spp.⁵⁰ is currently lacking, these findings suggest a potential pathway for its stable inheritance and vertical transmission in the future, which could complement plasmid-mediated horizontal dissemination and lead to more persistent resistance reservoirs.

Co-Localization with Other Drug Resistance Genes

Carbapenem-resistant Salmonella Typhi (CR Salmonella enterica var typhi) commonly exhibits a broad spectrum of resistance, primarily characterized by an extensively drug-resistant (XDR) phenotype, which includes resistance to ampicillin, chloramphenicol, TMP-SMX, fluoroquinolones, and third-generation cephalosporins (such as ceftriaxone), as well as carbapenems. Whole-genome sequencing analysis revealed that bla_NDM-5 often coexists with other resistance genes, including bla_CTX-M-15, which is the most prevalent and mediates resistance to third-generation cephalosporins.^9,51 Some strains carry both bla_TEM-1 and bla_SHV type β-lactamase genes.^10,51 Mutations in the QRDR region: gyrA (Ser83Phe, Asp87Asn/Gly) and parC (Ser80Ile) mutations lead to high levels of resistance;^51,52 Plasmid-mediated resistance genes: qnrS, aac(6′)-Ib-cr,^51,53 Chloromycetin resistance: catA1/b3; Sulfonamide resistance: sul1/sul2/sul3; trimethoprim resistance: dfrA7/14/27; aminoglycoside resistance: aac(3)-IV, aadA1.^43,53 A strain of Salmonella Typhi isolated in India was found to simultaneously harbor bla_NDM-5 and aac(6′)-Ia genes.⁹ This co-localization phenomenon enhances the multidrug resistance of bacteria, posing a greater challenge for clinical treatment. Additionally, bla_NDM-5 positive strains typically carry the gyrAS83Y mutation associated with fluoroquinolone resistance,⁹ further limiting treatment options. In certain cases, the bla_NDM-5 gene coexists with the mcr-1 mediated colistin resistance gene,⁵⁴ resulting in an extremely drug-resistant phenotype that poses a serious threat to public health.

Molecular Mechanism of Drug Resistance Transmission

Horizontal Gene Transfer

The bla_NDM-5 gene is mainly located on plasmids. These plasmids are highly transferable and can be transmitted between different bacteria through conjugation. Common plasmid types include IncX3,⁵⁵ IncHI2,⁵⁶ IncFI.⁵⁷ Whole-genome sequencing analyses have revealed that this gene is often located on InCX3-type plasmids and co-localizes with resistance genes such as aac(6′)-Ia.⁴⁵ The positioning of insertion sequences IS3 and IS30 in the 5 kbp adjacent region of the bla-ble gene cluster indicates that transposon-mediated horizontal gene transfer is an important mode of dissemination.⁵⁸ The IncY plasmid p60006, identified in Indian isolates, does not carry the carbapenemase gene; however, its presence confirms the potential for plasmid-mediated resistance transmission.¹¹ Additionally, the bla_NDM-5 gene can be amplified in multiple copies through IncFIA/FIB/IncFII plasmids, and this gene dosage effect significantly enhances the resistant phenotype.⁴¹

Vertical Transmission of Chromosomes

Although the bla_NDM-5 gene is mainly present in plasmids, it has also been reported that it can be integrated into bacterial chromosomes. For example, in Escherichia coli, the bla_NDM-5 gene is associated with insertion sequences such as IS26 and IS91, forming the structure of “IS26-bla_NDM-5-ble_MBL-trpF-IS91”.^59,60 This chromosomal integration further increases the stability and transmission potential of the bla_NDM-5 gene. The bla_NDM-5 gene carried by the chromosome can be stably inherited and co-evolve with chromosomal resistance markers such as the gyrAS83Y mutation.⁴⁵ Notably, certain isolates carried antibiotic resistance plasmids; however, no antimicrobial resistance gene clusters were found on the chromosome. This suggests that the loss of plasmids may lead to phenotypic reversion (Figure 5).^11,61

Figure 5 Both the IncFIA/IncFIB/IncFII consensus plasmid and the characteristics of the blaNDM-5-containing translocatable unit that were characterized from isolates 1–5 are summarized. Reproduced with permission. Copyright 2022, Clin Infect Dis.41

Environment-Animal-Human Cross-Host Transmission

In monitoring conducted in China, two bla_NDM-5 positive enteric Salmonella strains were detected among 3695 Salmonella isolates, confirming the presence of antibiotic-resistant bacteria in the environment.⁶² The study of the transmission patterns of the mcr-9 gene in avian-derived S. Thompson strains provides a model for understanding the interspecies dissemination of antibiotic resistance genes.⁶³ Monitoring of carbapenem-resistant Enterobacteriaceae in Thailand revealed that identical plasmids can be transmitted between different bacterial species, confirming gene flow at the environmental-clinical interface.⁶⁴ NDM-5 positive Escherichia coli, Klebsiella pneumoniae, and Citrobacter spp. isolated from environmental samples and human feces exhibited the same antibiotic resistance plasmid profile, providing direct evidence of the transmission chain of resistance.⁶⁵

Advances in Diagnostic Techniques and Surveillance Methods

The effective management of CR Salmonella enterica var typhi hinges on rapid, accurate diagnosis and robust surveillance. Technological advancements have enhanced capabilities across the entire spectrum, from phenotypic confirmation to genomic epidemiology.

Phenotypic Examination

For the phenotypic detection of bla_NDM-5 positive Salmonella Typhi, the Vitek ID/(Antimicrobial Susceptibility Testing) AST system is widely used for preliminary identification and to profile resistance to critical antibiotics, such as carbapenems (eg, meropenem), third-generation cephalosporins (eg, ceftriaxone), and fluoroquinolones (eg, ciprofloxacin).^66,67 Notably, these strains typically exhibit a multidrug resistance pattern to ampicillin, ciprofloxacin, ceftriaxone, tetracycline, and meropenem, while remaining sensitive to azithromycin, chloramphenicol, and trimethoprim-sulfamethoxazole.^65,66 Serological typing serves as a supplementary diagnostic method to confirm the serotype of Salmonella Typhi.⁶⁶

Molecular Detection

Molecular detection technologies for bla_NDM-5 have rapidly developed. Online applications such as Pathogenwatch can quickly identify antibiotic resistance markers in genomes, and their clustering analysis is comparable to traditional bioinformatics methods.⁶⁸ Whole genome sequencing technologies, such as the Illumina platform, can simultaneously detect the presence of resistance genes such as bla_NDM-5 and aac(6′)-Ia, as well as the IncX3 plasmid.^9,66 In a large-scale study conducted in Singapore, whole-genome sequencing was successfully applied to the analysis of 222 carbapenem-resistant non-susceptible strains, identifying multilocus sequence typing and antibiotic resistance gene profiles.⁶⁹ These technologies hold significant value for the early detection of outbreaks of NDM-5 positive strains.^9,64

Whole Genome Sequencing (WGS)

Whole-genome sequencing (WGS) provides the most comprehensive information, including all known and potentially unknown resistance genes, mutations, plasmid types, serotypes, multilocus sequence typing (MLST), and single nucleotide polymorphism (SNP) typing for high-resolution phylogenetic analysis. It has become a key tool for studying the transmission of antibiotic resistance in Salmonella Typhi.

Outbreak Investigation and Source Tracking

In outbreak investigations, WGS can accurately identify the phylogenetic relationships between strains, such as the close association between an Indian isolate and the 2016 XDR outbreak strain from Pakistan.^9,65

Unveil Transmission Dynamics

Through the genomic analysis of 3489 strains of Salmonella enterica serovar Typhi, researchers were able to trace the spatiotemporal transmission patterns of antibiotic-resistant strains,^25,70 while studies in Malawi used WGS to find the H58 genotype similarity between cases and isolates from carriers (Figure 6). ^71,72

Figure 6 (a) Monthly distribution of Salmonella enterica var typhi genotypes in cases. (b) Monthly distribution of Salmonella enterica var typhi genotypes in carriers. Note that counts include all culture-positive Salmonella enterica var typhi participants and those culture-positive for other Salmonella but later identified as Salmonella enterica var typhi by WGS. Multiple introductions of multidrug-resistant typhoid associated with acute infection and asymptomatic carriage, Kenya. Reproduced with permission. Copyright 2021, eLife.

Discover Novel Resistance Mechanisms

WGS plays an irreplaceable role in identifying novel antibiotic-resistant plasmids (such as IncFII(Yp)) and tracking cross-regional transmission chains.^35,67 Large-scale studies, such as one analyzing 222 carbapenem-non-susceptible isolates in Singapore, demonstrate its power in defining population structure and resistomes.⁶⁹

Clinical Treatment Challenges

Clinical Manifestations and Treatment Challenges

Carbapenem-resistant Salmonella enterica serotype Typhi (CR Salmonella enterica var typhi) causes typhoid fever. Although the cardinal symptoms (persistent high fever, relative bradycardia, rose spots, and hepatosplenomegaly) are indistinguishable from those caused by non-resistant strains, the risk of severe complications—including intestinal hemorrhage, perforation, toxic encephalopathy, and septic shock—is significantly increased. The increased severity is primarily attributed to diagnostic delays (due to insufficient sensitivity of laboratory tests) and delays in effective antimicrobial treatment.

Epidemiological data indicate that a treatment delay of more than 72 hours can increase the risk of intestinal perforation.⁷³ Owing to widespread resistance to frontline antibiotics (such as ampicillin, compound sulfamethoxazole, chloramphenicol), fluoroquinolones (such as ciprofloxacin), and third-generation cephalosporins (such as ceftriaxone), traditional treatment regimens have failed. The subsequent misuse of ineffective antibiotics exacerbates treatment delays, driving the increased incidence of complications (such as intestinal perforation and neurological symptoms), and elevated mortality rates, which can reach up to 26% in untreated cases.⁷³ In a case reported from Pakistan, strains initially susceptible to carbapenems and azithromycin acquired the bla_NDM-5 gene during treatment, resulting in ultimate treatment failure.⁷⁴ This dynamic evolution of drug resistance poses a significant challenge to clinical treatment, particularly in resource-limited areas.⁷⁵

Adverse Prognosis

Consequently, CR Salmonella enterica var typhi infection is associated with a profoundly worse prognosis compared to non-resistant or MDR/XDR (non-CR) typhoid fever. The cascade of treatment delays and failures results in markedly prolonged hospitalization, with the average length of hospital stay extended by 2 to 3 times, and a 5 to 10-fold increase in direct medical costs),^12,53 critically elevating mortality rates. Although the specific mortality rates vary due to patients’ baseline conditions, severity of infection, timeliness of treatment, and effectiveness of treatment protocols, multiple studies have reported that the mortality rate associated with CR infections is elevated by 3–5 times compared to sensitive strains. For instance, a study conducted in Pakistan indicated that the mortality rate for CR infections reached 15–20%, whereas infections with sensitive strains only accounted for 1–2%.⁷⁶

Therapeutic Strategies and Future Outlook

The management of CR Salmonella enterica var typhi infections necessitates a multifaceted approach, combining current clinical strategies with innovative research to overcome the challenges of extensive drug resistance.

Current Cornerstone: Combination Therapy

In the absence of reliably effective monotherapy, combination therapy has become the clinical mainstay. Intravenous administration of meropenem in combination with polymyxin has proven effective in treating infections caused by bla_NDM-5 positive Salmonella Typhi.⁷⁴ Notably, in numerous reported cases of multidrug-resistant Salmonella Typhi in Canada, the United States, and Europe, all isolated strains exhibited resistance to ampicillin, ceftriaxone, ciprofloxacin, and trimethoprim-sulfamethoxazole, underlying the importance of combination therapy strategies.⁷¹ However, therapy must be guided by AST, as evidenced by cases from India where strains carrying bla_NDM-5 unexpectedly retained susceptibility to carbapenems, highlighting the critical need for individualized treatment plans.¹¹

Innovative Approaches

Significant progress has been made in developing novel β-lactamase inhibitors against bla_NDM-mediated carbapenem resistance. Ceftazidime-taniborbactam, a β-lactam/β-lactamase inhibitor combination under investigation, demonstrates good activity against Enterobacteriaceae expressing serine and metallo-β-lactamases.⁷⁷ Silencing resistance genes, as demonstrated by the significant reduction in resistance observed upon silencing the bla_NDM-1 gene in Klebsiella pneumoniae, provides a novel theoretical framework for antibacterial development.⁷⁸

Novel Antimicrobial Strategies

Research is increasingly focused on innovative strategies that disarm bacterial defenses or enhance drug delivery to the site of infection. In drug delivery systems, novel macrophage-targeted mannose-modified hyaluronic acid precursor drug delivery systems have demonstrated potential for treating Salmonella Typhi infections.⁷⁹ These innovative approaches provide new treatment options for infections caused by bla_NDM-5 positive Salmonella Typhi.⁸⁰ Recent research from Cornell University has demonstrated that rifampicin, a widely utilized antibiotic, exhibits up to 99.9% efficacy against multidrug-resistant Salmonella enterica var typhi. This therapeutic potential is attributed to its capacity to effectively disassemble the bacterium’s protective capsule.²⁷ The bacterial capsule plays several critical roles in pathogenesis, including mediating immune evasion, facilitating host cell invasion and biofilm formation, and directly obstructing antibiotic penetration. Rifampicin effectively dismantles the Vi capsule of Salmonella enterica var typhi, compromising the pathogen’s defenses and enhancing its clearance. This mechanism not only offers a novel therapeutic approach for addressing drug-resistant typhoid fever but also has broader implications. It is highly anticipated that it could significantly broaden the application potential of rifampicin.²⁷

Public Health Prevention and Control

Drug Resistance Monitoring Network Optimization

The emergence of bla_NDM-5 positive Salmonella Typhi strains represents a significant threat to public health, underscoring the necessity for a comprehensive antimicrobial resistance monitoring network. First, it is essential to enhance the application of whole-genome sequencing technology for outbreak tracing.⁷⁷ Genomic epidemiological studies enable the investigation of transmission pathways and evolutionary relationships among antibiotic-resistant strains. Additionally, it is essential to establish a comprehensive surveillance system that encompasses hospitals, communities, and the environment, with a particular focus on bla_NDM-5 positive strains carrying plasmids such as InCX3.^40,80 In addition, it is necessary to develop a web-based pathogen monitoring platform, such as the PathogenWatch system, to enable the rapid identification of antibiotic resistance genes and real-time comparison of public genomic data (Figure 7).⁶⁸ Notably, bla_NDM-5 positive bacterial strains have been identified in China,⁸¹ indicating the need to strengthen regional monitoring cooperation and establish a cross-regional information-sharing mechanism for antibiotic-resistant strains.

Figure 7 The distribution of ciprofloxacin minimum inhibitory concentration (MIC) values, genotypic AMR predictions, and abundance differences of genetic mechanism combinations in Salmonella enterica var typhi isolates using PathogenWatch system are summarized. Reproduced with permission. Copyright 2021, Springer Nature.

Infection Prevention and Control (IPC)

Comprehensive multi-layered measures should be adopted for the prevention and control of infections caused by bla_NDM-5 positive Salmonella Typhi. In medical institutions, strict contact isolation measures should be implemented, particularly for patients from endemic areas, such as India and Pakistan.^31,82 Given that this strain can be transmitted through the environment-animal-human pathway,⁶⁵ it is necessary to enhance environmental disinfection in hospitals and manage medical waste. In terms of community prevention and control, it is essential to improve health infrastructure, particularly in areas where typhoid fever is endemic, to reduce the risk of fecal-oral transmission.⁸³ International travelers are recommended to receive a typhoid vaccine before visiting popular areas and to enhance health monitoring after returning home.⁸³ In addition, rapid diagnostic technologies, such as molecular detection methods, should be established to achieve early identification of the bla_NDM-5 gene, providing a basis for timely preventive and control measures (Figure 8).⁴⁰

Figure 8 Both the IncX3 plasmid carrying blaNDM and the regulatory processes of T4SS-mediated conjugation (including hppX3-dependent repression in State 1 and actX/virBR-triggered activation in State 2) are summarized. Reproduced with permission Copyright 2025, Oxford Academic.

Antibiotic Management (AMS)

In the face of bla_NDM-5-mediated carbapenem resistance, stringent antibiotic management strategies must be implemented. Firstly, the clinical use of carbapenems should be restricted, reserving them as a last resort for the treatment of multidrug-resistant typhoid fever.⁸⁴ Furthermore, it is recommended that precision medication plans be developed based on drug susceptibility results. For example, in the case of bla_NDM-5 positive strains, a treatment regimen combining meropenem and polymyxin may be considered.⁸⁴ In popular areas, it is essential to establish a monitoring system for antibiotic use, with a particular focus on currently effective drugs, such as azithromycin.^31,85 In addition, it is essential to enhance the training of healthcare professionals to improve their ability to identify drug-resistant typhoid and standardize their awareness of medication use. Finally, the development of novel β-lactamase inhibitors should be encouraged to provide more options for clinical treatment.⁸⁵ Notably, antibiotic management strategies should be combined with vaccination measures to form a comprehensive prevention and control system.⁸³

Conclusion and Future Perspectives

Carbapenem-resistant Salmonella Typhi, particularly strains carrying the bla_NDM-5 gene, represents an escalating global public health threat due to its high pathogenicity, extensively drug-resistant profile, and transregional transmission capacity. The ongoing spread is driven by horizontal gene transfer via epidemic plasmids such as IncX3 and IncHI2, often in conjunction with resistance to fluoroquinolones and cephalosporins, severely limiting treatment options. Although combination regimens like meropenem with polymyxin offer temporary efficacy, treatment failure and mortality remain high, underscoring the urgent need for novel therapeutics and robust antimicrobial stewardship. Sustainable control demands an integrated approach encompassing genomic surveillance, rapid diagnostics, and strengthened infection prevention. Crucially, global collaboration is indispensable to coordinate surveillance, share data, and accelerate the development of innovative interventions, thereby fortifying defenses against this emerging challenge in the post-antibiotic era.